October 1964 Volume 3, Number 5 INVESTIGATIVE OPHTHALMOLOGY

Symposium on therapy: Complications and management

Cardiovascular renal agents as they impinge on ophthalmic practice

John E. Harris

I t is the purpose or this review to discuss that this does not produce additive effects the effects of cardiovascular renal agents as which may be toxic. they may relate to ophthalmic practice. While the drugs in general are grouped Antihypertensive agents according to their major therapeutic use, The past decade and a half has seen the I should like to emphasize within this synthesis of many antiarterial hypertensive framework, first, those which are used by agents as well as the isolation of the active the ophthalmologist in the treatment of principles of certain natural products. ocular disease; second, those which may Table I by no means lists all the agents have an effect on the eye, but which are which have been developed, nor is the not primarily used in the treatment of classification necessarily descriptive of the ocular disease; and, third, the toxicity which mode of action of the drug. Particularly may result from either the systemic use this is true of the first and third groupings. of agents employed for ocular conditions Under the first classification, that of or the combination of these with cardio- drugs acting at or near peripheral nerve vascular renal drugs which the patient is endings, we are dealing with a variety of taking for other reasons. Particularly the agents which have quite different modes latter deserves mention. Often the patient of action. I have included, for its historic presents with multiple vials of pills he is interest, Dibenamine, an example of adren- taking. It is the responsibility of the oph- ergic blocking agents, which, incidentally, thalmologist who may place this patient are no longer in favor in the treatment of on some systemic medication to be certain hypertension. Dibenamine was the first of its type made available for study, and second it was the first of the systemic From the Department of Ophthalmology, Univer- agents, excluding the osmotic agents, which sity of Minnesota Medical School, Minneapolis, enjoyed at least some temporary success Minn. in the treatment of glaucoma. Christensen 481

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Table I. Some antihypertensive agents in There are newer drugs which exert a current use peripheral effect somewhat similar to that of the Rauwolfia derivatives. Among these I. Act at peripheral nerve endings Dibenamine (not in use) are guanethidine (Ismelin) and bretylium Guanethidine (Ismelin) tosylate (Darenthin). These drugs affect Bretylium tosylate (Darenthin) only the sympathetic nervous system and Reserpine have been found to be of value in the Alpha methyldopa (Aldomet) Pargyline HC1 (Eutonyl) treatment of hypertension. They produce a similar clinical effect, although their II. Ganglion blocking agents modes of action may differ. Thus guanethi- Tetraethylammonium chloride (Etamon) Hexamethonium chloride (Bistrium) dine is a norepinephrine depleter whereas Pentolinium tartrate (Ansolysen) bretylium tosylate is not. Of these, guan- Mecamylamine (Inversine) ethidine is of particular interest since it has 111. Others been shown to lower the intraocular pres- Hydralazine (Apresoline) sure. While it reduces the norepinephrine Reserpine at the nerve endings and blocks the effect Veratrum preparations of nerve stimulation, it does not block the action of injected norepinephrine or epi- nephrine. Indeed, the pressor effect of these and Swan first reported the value of this agents is actually greater in the animal pre- drug as an ocular hypotensive agent. treated with guanethidine. In this respect Others corroborated this report. The agent the action of the drug simulates a surgical (no longer available) had to be admin- sympathectomy. istered intravenously and this made its use Guanethidine has been shown to pro- limited. Nonetheless, it proved of value in duce a delayed miosis and drop in ocular certain cases of acute glaucoma which did tension in the rabbit. Our own experience not respond to standard treatment. The in the laboratory indicated that the drug mode of action of this agent is not certain had no effect on the intraocular pressure but it appears to reduce the rate of aqueous of the normal cat when administered topi- formation. cally or injected into the internal maxillary The Rauwolfia alkaloids occupy an in- artery. It did produce a drop in the in- teresting position among the antihyperten- traocular pressure when injected into the sive agents. Of these perhaps the most femoral vein but this paralleled the fall in widely used is reserpine. It is among the the arterial blood pressure and presum- group of antihypertensives that is known ably was caused by it. However, ours were to deplete the body stores of norepineph- acute experiments. In humans, adminis- rine. Because it produces alterations of tered topically either alone or as an adju- mood and behavior, it originally was vant, it does lower the intraocular pressure thought to exert its arterial hypotensive in glaucomatous eyes. We were originally action via the central nervous system. The quite enthusiastic, but now feel that it view is logical since reserpine is known to offers little improvement over standard reduce the central nervous system stores forms of topical therapy. There would ap- of norepinephrine. The drug has also been pear to be no contraindications to the found to deplete peripheral stores of nor- combined uses of any of these agents and epinephrine and therein may hinge its the systemic agents which the ophthalmol- mechanism of action as an antihyperten- ogists might employ. sive. Of the drugs which the ophthalmol- The enzyme inhibitors present an in- ogists may use systemically, there is none teresting group of antiarterial hyperten- which could not be readily combined with sives. One group consists of the decarboxy- the Rauwolfia derivatives. lase inhibitors of which the principal one

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is alpha methyldopa (Aldomet). It blocks ness have resulted from a too profound the decarboxylation of aromatic amino depression of the systemic blood pressure acids and consequently reduces the pro- by these drugs, usually at surgery. Their duction of catecholamines, including nor- mixture with agents that ophthalmologists epinephrine and serotonin. In spite of the might use should produce no harmful ad- good biochemical data and inferences, the ditive effects. exact mechanism by which this enzyme in- The other drugs have varied sites of ac- hibitor influences hypertension is not tion. The effect of hydralazine, once known. Alpha methyldopa has been tested thought to be central, is now considered to for possible ocular hypotensive action with be directly on the smooth muscle of the both topical and systemic routes of ad- arterioles. The effect of the veratrum deriv- ministration and has been found to have atives has been shown to be on the baro- little or no effect. There would appear to ceptors and chemoceptors of the carotid be no contraindication to the combined use sinus, the aortic arch, etc. These drugs of this agent and those which an ophthal- have no use in the treatment of ocular mologist might employ. disorders, although presumably they would An even more interesting example of en- lower the intraocular pressure by virtue zyme inhibition of arterial hypertension is of their effect on the blood pressure. There that of the inhibitors of monoamine oxi- is no contraindication to their use in the dase. The enzyme itself sometimes has been treatment of ophthalmic disorders. regarded as the one responsible for the Before leaving the antihypertensive in activation of epinephrine and norepi- agents, I would like to consider the ques- nephrine. This does not seem to be the tion of arterial hypertensive crises which case. The inhibitors of this enzyme, of the ophthalmologist may encounter. Very which pargyline HC1 (Eutonyl) is an ex- rarely is it necessary for the ophthalmolo- ample, cause postural hypotension. They gist to treat these conditions, but, occasion- seem to exert their effect by preventing ally, particularly postsurgically, a hyper- the release of norepinephrine at sympa- tensive crisis may result that requires treat- thetic nerve endings in a manner which is ment. There is a variety of agents that not understood and, indeed, may not even might be used for this purpose. These be related to the inhibition of the enzyme. have largely been covered by Gifford. We The ganglion blocking agents have been have preferred reserpine, giving it general- fairly extensively employed. They are po- ly intravenously although intramuscular in- tent hypotensive agents. These drugs block jection is probably just as adequate. Re- both parasympathetic and sympathetic serpine does not reduce the blood pressure ganglia and thus have the unwanted side as rapidly as many of the other agents. effect of blocking the parasympathetic ner- Thus, readministration of this drug, if a vous system. This would appear to accoimt more profound effect is desired, should be for one of the undesirable side effects of delayed for one to two hours, lest the pa- these agents, i.e., blurring of vision, an tient suffer too great a drop in blood pres- effect, incidentally, which is reported to be sure. blocked by pilocarpine. They have been Perhaps a more commonly encountered reported to lower the intraocular pressure. condition is the hypotensive crisis. This Presumably this is due to the drop in blood usually presents to the ophthalmologist pressure but this cannot be stated with cer- when the patient arrives at the operating tainty. Their use for this purpose would room and may be the result of the pre- certainly be infrequent. The only instance operative medications. The usual support- might be in an acute glaucomatous eye ive therapy is indicated of course. There when other therapy has failed. It is of are a number of agents which can be given interest to note that certain cases of blind- intravenously or even intramuscularly for

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Table II. Diuretics raised. Nonetheless, if the view is correct, the cardiac glycosides should inhibit aque- Organic mercurials Carbonic anhydrase inhibitors ous flow and cause a reduction in ocular Benzothiadiazines tension. This, indeed, has been reported Aldosterone antagonists and digoxin has been suggested for use in Osmotic agents the treatment of the glaucomas that are resistant to the standard therapeutic methods. Considering the toxicity of the Table III. Organic mercurials digitalis derivatives, this form of therapy for glaucoma does not have much to com- Chlormerodrin (Neohydrin) mend it. The suggested use of digoxin com- Meralluride (Mercuhydrin) bined with carbonic anhydrase inhibitors Mercaptomerin sodium (Thiomerin) Mercumatilin (Cumertilin) should also be approached with caution Meretholylline (Mercuzerthin) since the latter promotes potassium diure- Merethoxylline (Dicurin) sis. The digitalized heart is peculiarly sen- Mersalyl and theophylline (Salyrgan) sitive to hypokalemia, cardiac arrhythmias being produced.

this purpose. The drug which we have Diuretics found most useful has been Aramine in The major groups of diuretics that are doses of 1 mg., fairly slowly, given intra- presently used are listed in Table II. The venously while following the blood pres- listing is not complete. The organic mer- sure of the patient. The dose can be re- curials (Table III) have been used with peated if necessary. consistent success in instances where di- uretics are indicated. Presumably the di- Cardiac glycosides uretics poison an enzyme of the kidney The exact mechanism by which digitalis tubules which is necessary for the reab- and its derivatives stimulate cardiac muscle sorption of sodium chloride from the glo- is not known. These compounds, the car- merular filtrate. The diuretic induces both diac glycosides, have profound effects at sodium and chloride excretion. There may the cellular level. Among these is an in- be a slightly greater excretion of chloride hibition of Na-K ATPase. This enzyme than sodium to the extent that the patient mediates the transport of cations across may develop a hypochloremic alkalosis. cellular barriers in such a manner that There is no appreciable diuresis of potas- potassium is concentrated within a cell sium. The diuretics do not reduce the in- and sodium is excreted from it. The inhi- traocular pressure and consequently have bition of the enzyme by the cardiac gly- no value in the treatment of glaucoma. In coside results in a depletion of cellular general, there is no contraindication to the potassium and a gain in cellular sodium. combined use of carbonic anhydrase in- The depletion of potassium from the dig- hibitors or other agents the ophthalmol- italized heart is well known. It is not in- ogists might use and the organic mercurials. tended to imply that the depletion of po- Similarly the organic mercurials do not tassium is responsible for the inotropic alter the action of the carbonic anhydrase action of digitalis. inhibitors on the ciliary epithelium. The ciliary body is among the tissues The carbonic anhydrase inhibitors are a that contain the enzyme, and it may medi- chronologically newer group of diuretics. ate the transfer of sodium from the plasma A search for such agents was based on the to the posterior chamber and thus play a knowledge that an exchange of hydrogen role in the formation of aqueous humor. for sodium in the urinary tract requires Certain objections to this view can be carbonic acid and carbonic anhydrase. The

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Table IV. Various carbonic anhydrase inhibitors of ophthalmic interest

Generic name \ Trade name \ Mg./tablet \ Usual close/day (mg.) Acetazolamide Diamox 250 250-1,000 Dichlorphenamide Daranide 50 50-300 Methazolamide Naptazane 50 100-400 Ethoxzolamide Cardrase 125 125-500

carbonic anhydrase inhibitors promote the Table V. Side effects of carbonic anhydrase diuresis of sodium with chloride and, in inhibitors addition, a diuresis of bicarbonate and po- Pares tli esias tassium. The diuresis of bicarbonate causes Anorexia a drop in the bicarbonate level of the Gastrointestinal upset plasma and a systemic acidosis. This ul- Loss of weight timately limits the effectiveness of the car- Abdominal crises Skin rash bonic anhydrase inhibitors as diuretics. The Agranulocytosis drugs are thus most valuable in conditions Headache other than those requiring chronic ad- Disorientation Depression ministration of diuretics. Hypokalemia Among these conditions is the treatment of glaucoma, which was originally reported by Becker approximately one decade ago. Table VI. Benzothiadiazines The compounds available are listed in Table IV. The idea that carbonic anhydrase Chlorothiazide (Diuril) is involved in the secretion of aqueous Hydrochlorothiazide (HydroDiuril, Esidrix, Oretic) Flumethiazi.de (Ademol) fluid was implicit in the theory of aqueous Hydroflumethiazide (Saluron) formation advanced by Freidenwald. While Bendroflumethiazide (Naturetin) the exact mechanism by which the enzyme Benzthiazide (NaClex) Methyclothiazide (Enduron) mediates the formation of aqueous is not Poly thiazide (Renese) known, it has been abundantly proved that Trichlormethiazide (Naqua) the carbonic anhydrase inhibitors exert their ocular hypotensive effect by reducing the rate of aqueous formation. They ap- effects while maintaining effective clinical pear to act directly on the ciliary body. management of the glaucoma. However, by Thus, the hypotensive response does not and large, intolerance to one is also ac- appear to be due to altered chemistry of companied by intolerance to another in the blood or to some other metabolic effect full therapeutic doses. There are certain audistance. Multiple studies, both static exceptions to this. The compounds do in- and dynamic, of the chemical changes in- duce a typical sulfonamide type of skin duced in the plasma and aqueous of many rash. Upon switching to an agent that has species by these enzyme inhibitors have a different structure, e.g., from acetazol- been made. amide to dichlorphenamide, the skin may The side effects of the carbonic anhy- clear and the patient be continued on a car- drase inhibitors are well known. (Table V). bonic anhydrase inhibitor. Generally, in, clinically effective dosages, There is one side effect that I think de- the various carbonic anhydrase inhibtors serves greater emphasis. The carbonic an- induce much the same side effects. On oc- hydrase inhibitors are kaluretic agents and casion it is feasible to switch from one in- induce a hypokalemia. Generally, the car- hibitor to another and reduce the side bonic anhydrase inhibitors are prescribed

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to individuals in the older age group. These tion is not known. They compete with the patients may also be taking other kaluretic organic mercurials and to a certain degree agents, such as the thiazide derivatives or also with the carbonic anhydrase inhibitors, steroids. Such combinations may depress but in each instance, however, they have the serum potassium to the extent that the an additional site of action. They, like the patient may have symptoms of hypokale- organic mercurials can cause the low salt mia, such as weakness, generalized malaise, syndrome. Their kaluretic effect is cer- gastrointestinal disturbances, and thirst. In tainly observed in acute administration, addition, if the subject is digitalized, car- however, there is some suggestion that in diac arrhythmias may develop. The prob- chronic administration they might not de- lem is usually solved by adding potassium plete the body potassium appreciably al- to the regimen. We generally have pre- though hypokalemia will persist. When ferred potassium bicarbonate, and some prescribing a carbonic anhydrase inhibitor have even suggested that this may enhance to a patient who is already receiving one the effect of the drug on the ciliary epi- of the thiazide derivatives, it is well to be thelium. Potassium chloride can be used. on the lookout for hypokalemia. I might When the individual is subjected to some add that these drugs do not lower intra- stress that might reduce the blood pressure, ocular pressure. or if there is a hepatic failure, the amount I should like to mention in passing one of circulating aldosterone might increase. of the newer groups of drugs, namely, the This will promote potassium diuresis and aldosterone antagonists. These are the further deplete the body stores of potas- spirolactones and the compound now avail- sium. I have been involved in one instance able is spironolactone (Aldactone). Aldo- in which the patient became ill of an un- sterone inhibits the excretion of sodium and diagnosed condition while on both steroids promotes potassium diuresis. Spironolac- and dichlorphenamide. The case was tone, therefore, reduces potassium loss and finally diagnosed pneumonia, but this was promotes sodium excretion. The drug is done at autopsy. During the course of the effective only in the presence of aldoste- illness the serum potassium fell to below rone or other steroids having similar action. 2 mEq. per liter and the bicarbonate to It appears to be quite effective when used below 5 mEq. per liter. Certainly all of this in combination with other diuretics. Spiro- cannot be attributed to the medications the nolactone has been reported to reduce patient was receiving, but they may have aqueous formation in the rabbit. There been a factor. would appear to be no contraindication to There are few contraindications to the its use with carbonic anhydrase inhibitors. use of the carbonic anhydrase inhibitors. Indeed, it may be of value since it reduces They can be prescribed to patients mani- kaluresis. festing fairly severe renal failure. They The osmotic agents have had a resur- should be used with circumspection in gence in ophthalmic therapy, particularly patients who may have severe electrolyte since the studies of Javid on the use of in- imbalance, e.g., following prolonged eme- travenous urea in patients with cerebral sis, and should not be used in patients with edema. Urea readily penetrates the red adrenal failure. cell and when used in even hypertonic The benzothiadiazine or thiazide deriva- concentrations causes a hemolysis. Hence, tives are widely used in medicine. Not only it is administered with some innocuous are they diuretics but they seem to have substance which does not readily penetrate an antiarterial hypertensive effect as well. the red cell and thus prevents the hemoly- These derivatives promote the excretion of sis. It can be given orally but this is some- sodium and chloride. They also promote what unpalatable and consequently is kaluresis. The exact mechanism of the ac- generally given intravenously as a 30 per

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cent solution in 10 per cent fructose, • Serum iI O.T. usually in doses of 1 to Wz Gm. per kilo- Mosm. Applanofion gram administered over a period of 30 to • 50 45 minutes. As such it has a profound ocu- 340 lar hypotensive effect. Urea has its greatest (Gonioscopy) ' N 40 3 benefit in acute glaucoma where standard 330 3 methods have failed and in surgical pro- 7> 30 I o - 'J' . ^ - - cedures where a particularly soft eye is 2 320 desired. There are no contraindications to / / Glycerol (Icc/kg) 20 using it in combination with carbonic an- till hydrase inhibitors. Its use is contraindi- 0 12 3^\ cated in individuals with severe renal or Hours hepatic dysfunction or in the presence of Narrow but open angle glaucoma marked dehydration. Other medication pilocarpine, epinephrine, The other agent currently used for simi- diamox lar purposes is a sugar alcohol, mannitol. Fig. 1. Effect of glycerol on ocular tension and This has almost three times the molecular serum osmotic pressure. weight of urea and because of limitations in its solubility, mannitol does not have the potential for lowering the intraocular The last agent to be discussed in this pressure that urea has. It is generally ad- regard is glycerol, which recently has been ministered as a 20 per cent solution (al- reported to be of value in the treatment though 25 per cent can be achieved with of glaucoma. It has not been administered heating) intravenously in doses of 1 to 2 intravenously to my knowledge, although Gm. per kilogram over a period of 30 to this would be feasible providing some 45 minutes. There are no particular con- sugar or sugar alcohol such as mannitol traindications to its use. was given with it. Glycerol enters the red Among the side effects of the osmotic cell very rapidly and can cause hemolysis. agents are rather severe headache, dizzi- However, it can be very valuable when ness, and nausea. An overload of the car- taken orally with fruit juice. Generally, we diovascular system is feasible. Urea is ir- administer 1 c.c. per kilogram. There is ritating to the tissue and may cause phle- no reason why more could not be used. It bitis as well as local irritation if extravasa- is absorbed in the small intestine and does tion occurs. cause a rise in the osmotic pressure of the The mechanism of action of these agents serum and a drop in the intraocular pres- is generally considered to be simply os- sure (Fig. 1). It can be administered at motic, i.e., increasing the osmotic pressure home. The side effects are not marked. of the plasma with respect to that of aque- Since it is metabolized it does not promote ous promotes the movement of water from diuresis, and catheterization of the patient the eye. However, this may not be the is not necessary. sole effect of urea since we have found in our laboratory that, when administered Summary rapidly, urea may produce a very great Of the large number of drugs which rise in the osmotic pressure of the plasma come under the classification of cardio- and yet not lower the ocular tension of vascular renal agents, only a few, the car- the cat. Indeed, it may be raised. The bonic anhydrase inhibitors and the osmotic exact reason for this is not certain. I sim- diuretics, have general usefulness in oph- ply mean, to suggest that there may be an thalmic practice. However, a good portion additional mode of action of urea on the of the patients the ophthalmologist may be intraocular pressure. treating may be taking other cardiovascular

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renal drugs for other physical ailments. ognize the mode of action and side effects The drugs of this group most likely to be of these drugs, and the added toxicity encountered are the antiarterial hyperten- which may be induced by the therapy sives, the cardiac glycosides, and the vari- which he applies. ous diuretics. Ophthalmologists must rec-

Cover illustration Induction of differentiation, long known to embryologists as important in initial embryologic development, is possible even at later times. Here, in studies by V. Muthukkaruppan, a University of Wisconsin graduate student from India working in the laboratory of Dr. Robert Auerbach, the anterior lens epithelium from advanced mouse embryos has been isolated in tissue culture in combination with mesenchyme and neural retina. In the absence of neural retina, the anterior lens epithelium fails to differentiate. Addition of neural retina leads to induced development of a complete, new lens with oriented lens fibers. Note that the neural retina is separated from the lens epithelium by a thin millipore filter, indicating that some inductive material must pass from the neural retina during the inductive process. (Courtesy of Drs. V. Muthukkaruppan and R. Auerbach.)

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